The most serious complication of schistosomiasis is periportal fibrosis, which affects a large number of subjects in endemic areas. Population-based chemotherapy remains the most effective way of controlling this disease. In an attempt to find the best way to deliver chemotherapy to the endemic population, we compared the impact of repeated annual versus biennial mass chemotherapy on morbidity due to schistosomiasis in two villages in Gezira, Sudan. One village was given five rounds of mass chemotherapy annually in the years 1990-1994 while the other village was given three rounds of mass chemotherapy biennially from 1988 to 1994. Before treatment, these villages had similar intensity of infection and prevalence. One round of either annual or biennial treatment reduced the intensity of infection, but not prevalence or morbidity. After two rounds of annual chemotherapy, infection rates, bloody diarrhea, and fibrosis in those 20 years of age and less were significantly reduced. Two rounds of biennial chemotherapy had a similar effect on rates and bloody diarrhea; however, fibrosis was reduced only after the third round of biennial chemotherapy. Prevalence of hepatosplenomegaly increased after both treatment regimens. Reinfection was most prominent in those 5-14 years of age. These findings support the general notion that repeated chemotherapy may be needed in areas of high transmission of schistosomiasis. We recommend two rounds of annual mass chemotherapy to significantly reduce infection and morbidity.